The immune system is a defense system found in its most advanced form in higher vertebrates. This defense mechanism provides rapid and highly specific responses which are used to protect an organism against invasion by pathogenic microorganisms. It is the myriad of pathogenic microorganisms which have principally caused the evolution of the immune system to its current form. In addition to protection against infectious agents, specific immune responses are thought to be involved in surveillance against tumor development, the pathogenesis of autoimmune diseases, and transplant tissue rejection.
T cells are the major regulatory cells of the immune system. The regulatory functions of T cells depend not only on expression of a unique T cell receptor, but also on expression of a variety of accessory molecules and effector functions associated with an individual T cell response (i.e., a cytotoxic response versus a response characterized by secretion of effector molecules such as lymphokines). It is this regulatory function that often goes awry in the development of autoimmune diseases, plays a large role in tissue graft rejection, and can be important in tumor rejection.
Specificity of T cell responses is conferred by a unique set of cell surface receptors expressed on individual lymphocytes, called clonotypic T cell receptors (TCR). Cognate ligands of the clonotypic TCR are antigen major histocompatibility complex molecules (MHC). T cell receptors recognize antigens in the form of small antigenic peptides presented by MHC molecules on the surface of antigen presenting cells. While the interaction between an antigenic peptide and an MHC is quite stable, generally displaying a high affinity (10.sup.-9 M) and consequent long half-life of dissociation, the interaction between a T cell receptor and a peptideAMHC complex--the critical recognition event in triggering T cells--is of relatively low affinity, between 10.sup.-4 -10.sup.-6 M. As a result of this low affinity, the T cell response is driven by the interaction of many T cell receptors on the surface of an individual T cell interacting with multiple antigenic peptide/lHC complexes on the surface of the antigen presenting cell.
Antigen-specific T cells play major roles in normal physiologic immune responses and in many disease states. Hyperactivation of antigen-specific T cells targeted toward self antigens is the underlying basis for the majority of autoimmune diseases, including multiple sclerosis, arthritis, and diabetes. Conversely, inactivity of tumor antigen-specific T cells allows tumors to grow. Thus, activation of dormant or tolerant tumor-specific T cells has been a major goal of cancer immunotherapy. Other important medical phenomena, such as rejection of transplanted organs, depend on the activity of T cells specific for alloantigens expressed by these organs. Antigen-specific suppression of undesired T cell responses could potentially eliminate organ graft rejection.
The use of soluble monovalent reagents to monitor and modulate antigen-specific T cells is limited by the fact that T cell receptors interact with peptide/MHC complexes with relatively low affinities (28-30). Thus, soluble monovalent analogs of either T cell receptors or peptide/MHC complexes do not effectively regulate immune responses.
Soluble multivalent analogs of proteins involved in immune responses have been made. Such analogs include CD4/Ig chimeras (41, 42), CR2/Ig chimeras (43), and class I MHC/Ig chimeras (20). The influence of valence on ligand affinity of these analogs is variable. For example, CD4/Ig molecules do not have a higher affinity for their ligand than soluble monovalent CD4 molecules. Tetravalent peptide/MHC complexes have high affinity for specific T cell receptors. However, divalent MHC analogs do not have a high enough affinity to allow staining or regulating antigen-specific T cells. Thus, there is a need in the art for agents which can specifically induce or suppress T cells specific for antigens associated with infections, allergies, tumors, transplanted organs, and autoimmune diseases.